IL-6/STAT3 Inhibition Overcomes Cancer Stem Cell Resistance to Conventional Chemotherapy

Objectives: Cisplatin enhances the fraction of cancer stem cells (CSC) in head and neck squamous cell carcinoma (HNSCC), priming residual tumor cells for a more aggressive phenotype and leading to evasive resistance. IL-6 signaling enhances self-renewal and tumorigenic potential of CSC, which have been shown to mediate resistance and tumor recurrence. Our hypothesis is that therapeutic inhibition of the IL-6/STAT3 pathway will overcome CSC resistance to conventional chemotherapy.
Methods: Cisplatin-resistant HNSCC cell lines and control cells were exposed to Cisplatin and/or IL-6R inhibitor (Tocilizumab) in vitro. Patient-derived xenograft (PDX) models implanted in immunodeficient mice were treated with 0-5mg/kg Cisplatin and/or 0-5mg/kg Tocilizumab to assess therapeutic potential of combinatorial therapy. Tumors were assessed for differences in growth rates and tumor volume. The CSC fraction was analyzed by flow cytometry (ALDH, CD44) and orosphere assays, whereas expression of stemness markers was analyzed by western blot.
Results: Inhibition of IL-6/STAT3 signaling with Tocilizumab sensitized parental and Cisplatin-resistant HNSCC cell lines to Cisplatin therapy and reduced the CSC fraction. Tocilizumab treatment prevented Cisplatin-induced orosphere formation in vitro. Combination therapy decreased tumor growth rate, and reduced the Cisplatin-induced Bmi-1 expression and CSC fraction in vitro and in vivo.
Conclusions: Collectively, these data demonstrate that IL-6 signaling contributes to resistance to Cisplatin therapy in HNSCC and suggest a role for IL-6/STAT3 signaling in evasive resistance to chemotherapy. Our results suggest a novel treatment paradigm for HNSCC patients based on combination therapy with Cisplatin and an inhibitor of the IL-6/STAT3 pathway.